Over-expression of the amyloid precursor protein (APP) has been genetically proven as a direct cause of Alzheimer's disease in defined pedigrees in addition to more common APP processing mutation as that influences APP cleavage and Aβ peptide fibrilization (amyloid plaque formation). In addition, APP over-expression has been linked to Alzheimer's pathology of amyloidosis and dementia in older Down Syndrome (DS) patients. More recently genetic findings were reported that APP mutations can provide direct action to prolong life without dementia as much as other APP specific mutations at promoting neuronal death (Jonsson et al., Nature 2012, 488, 96-99).
In addition, increased levels of the metals iron, copper, zinc in the brain are associated with increased risk to accelerate the course of Alzheimer's disease (AD) (Lovell M A, et al., Neurol Sci 1998, 158: 47-52). To safely store excess iron, canonical iron-responsive elements (IREs) are the 5′UTR-specific RNA stem loops that control translation of L- and H-ferritin mRNAs (iron storage) so that the L- and H chains can assemble into this iron storage multimer. The iron-regulatory proteins (IRP1 (90 kDa) and IRP2 (105 kDa)) are the two known RNA-binding proteins that are key gatekeepers for cellular iron homeostasis because of their inducible interaction with IREs to control ferritin mRNA translation and transferrin receptor (TfR) mRNA stability (iron uptake) (Bandyopadhyay et al., Expert Opin Ther Targets 2011, 14: 1177-1197).
Consistent with the report that APP is an iron export ferroxidase (Duce J A, et al. Cell 2010, 691 142: 857-867), RNAi knockout studies showed that IRP1 binds strongly to 5′UTR sequences in the APP transcript to repress expression of the precursor (Cho H H, et al., Biol Chem 2010, 285: 31217-31232). In fact, the APP mRNA encodes an active IRE that binds with a different RNA-binding specificity to IRP1 relative to the IRE of ferritin mRNA (which interacts with IRP1 & IRP2). Thus the APP 5′UTR is a unique, highly specific drug target to identify APP (and Aβ) repressors. This model is consistent with a recent report that IRP1 outcompetes IRP2 in regulating cellular iron homeostasis in response to nitric oxide (Stys A, et al, J Biol Chem 2011, 286: 22846-22854).
The concept of repressing APP translation as a therapeutic strategy in DS and AD was proven as a novel anti-amyloid strategy as exemplified by the use of the APP 5′UTR-directed FDA drug N-acetyl-cysteine (NAC) in the TgCRND8 APP (Swe) mouse model of AD (Tucker et al., Curr Alzheimer Res. 2006, 3, 221-227). An additional benefit of limiting the APP levels may be to restore perturbations to iron homeostasis during DS since APP is over-expressed by one third on the DS trisomy chromosome 21 (Salehi A, et al., Neuron 2006, 51: 29-42). Increased APP may well alter brain iron homeostasis based on its capacity to bind ferroportin and export iron (Duce J A, et al. Cell 2010, 691142: 857-867). In this regard, mice that are trisomic for chromosome 16, the orthologue of human chromosome 21, over-express APP and are genetically shown to develop the DS phenotype because of a triplicated expression of the APP gene (Salehi A, et al., Neuron 2006, 51: 29-42; Salehi A, et al., Translational Medicine 2009, 1: 1-9). The progression of familial Alzheimer's disease (FAD) can be the result of a genetically inherited over-expression of the APP gene or by somatically induced non-disjunction events that cause APP to be over-expressed (Granic A, et al., Mol Biol Cell 2012, 21: 511-520; Hooli B V, et al., Neurology 2012, 78: 1250-1257; Rovclet-Lecrux A, et al. Nat Genet 2006, 38: 24-26).
Thus, in addition to the altered processing of APP and other risk factors (e.g., inflammation, metal-catalyzed oxidative stress (Lovell M A, et al., Neurol Sci 1998, 158: 47-52; Perry G, et al. Free Radic Biol Med 2002, 33: 1475-1479; Smith C D, et al., Natl Acad Sci USA 1991, 88: 10540-10543; Butterfield D A, Neuromolecular Med 2012, 13: 19-22), and the increased levels of apolipoprotein-E (Kwon O D, et al., Dement Geriatr Cogn Disord 2012, 30: 486-491; Wisniewski T, et al., Am J Pathol 1994, 145: 1030-1035) and α-1 anti-chymotrypsin (ACT) (Nilsson L N, et al. Cognitive Neurobiol Aging 2004, 25: 1153-1167)), simple elevation of APP levels is a sufficient genetic cause of DS and AD (Hooli B V, et al., Neurology 2012, 78: 1250-1257; McNaughton D, et al., Neurobiol Aging 2012, 33: 426 e413-421).
Currently, improved early diagnosis for AD has been sufficiently refined so that levels of β-amyloid protein & phosphorylated tau neurofibrillary tangle protein in the cerebrospinal fluid of MCI patients predicts the onset of AD with greater accuracy than ever before (De Meyer et al., Arch Neurol 2010, 67, 949-956). It is now critically needed to develop novel therapies for neurodegenerative disorders such as AD and DS.